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1.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295829

ABSTRACT

ABSTRACT Background Acute respiratory distress syndrome (ARDS) in COVID-19 has been associated with dysregulated immune responses leading to catastrophic inflammation. The activation pathways remain to be fully elucidated. We investigated the ability of circulating to induce dysregulated immune responses. Materials & Methods Calprotectin and high mobility group box 1 (HMGB1) were associated with ARDS in 60 COVID-19 patients. In a second cohort of 40 COVID-19 patients calprotectin at hospital admission was associated with serum levels of soluble urokinase plasminogen activator receptor (suPAR). A COVID-19 animal model was developed by intravenous injection of plasma from healthy volunteers or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. In separate experiments, mice were treated with a) the IL-1 receptor antagonist Anakinra or vehicle and b) Flo1-2a anti-murine anti-IL-1α monoclonal antibody or the specific anti-human IL-1α antibody XB2001, or isotype controls. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured. Results Calprotectin, but not HMGB1, was elevated ARDS. Higher suPAR readouts indicated higher calprotectin levels. CHallenge of mice with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNFα, IL-6, IFNγ and MPO. Anakinra treatment brought these levels down. Similar decrease was found in mice treated with Flo1-2a but not with XB2001. Conclusion Circulating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1α mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or specific inhibition of IL-1α.

2.
J Innate Immun ; : 1-11, 2021 Dec 01.
Article in English | MEDLINE | ID: covidwho-1546612

ABSTRACT

BACKGROUND: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. METHODS: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. RESULTS: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. CONCLUSION: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

3.
Crit Care Med ; 49(12): 2042-2057, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1522362

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019-related sepsis is still unclear; we aimed to describe this in a systematic review. DATA SOURCES: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). STUDY SELECTION: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019-related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. DATA EXTRACTION: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. DATA SYNTHESIS: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019-related sepsis prevalence was 77.9% (95% CI, 75.9-79.8; I2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3-36.4; I2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9-23.6; I2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3-90.7; I2 = 98%). CONCLUSIONS: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications.


Subject(s)
COVID-19/complications , Hospitalization/statistics & numerical data , Sepsis/etiology , Sepsis/virology , Humans , Intensive Care Units/statistics & numerical data , Multiple Organ Failure/etiology , Patient Admission/statistics & numerical data , SARS-CoV-2 , Sepsis/mortality , Severity of Illness Index
4.
Elife ; 102021 03 08.
Article in English | MEDLINE | ID: covidwho-1121691

ABSTRACT

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19. Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied. Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata. Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance. Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme. Clinical trial number: NCT04357366.


People infected with the SARS-CoV-2 virus, which causes COVID-19, can develop severe respiratory failure and require a ventilator to keep breathing, but this does not happen to every infected individual. Measuring a blood protein called suPAR (soluble urokinase plasminogen activator receptor) may help identify patients at the greatest risk of developing severe respiratory failure and requiring a ventilator. Previous investigations have suggested that measuring suPAR can identify pneumonia patients at highest risk for developing respiratory failure. The protein can be measured by taking a blood sample, and its levels provide a snapshot of how the body's immune system is reacting to infection, and of how it may respond to treatment. Anakinra is a drug that forms part of a class of medications called interleukin antagonists. It is commonly prescribed alone or in combination with other medications to reduce pain and swelling associated with rheumatoid arthritis. Kyriazopoulou et al. investigated whether treating COVID-19 patients who had developed pneumonia with anakinra could prevent the use of a ventilator and lower the risk of death. The findings show that treating COVID-19 patients with an injection of 100 milligrams of anakinra for ten days may be an effective approach because the drug combats inflammation. Kyriazopoulou et al. examined various markers of the immune response and discovered that anakinra was able to improve immune function, protecting a significant number of patients from going on a ventilator. The drug was also found to be safe and cause no significant adverse side effects. Administering anakinra decreased of the risk of progression into severe respiratory failure by 70%, and reduced death rates significantly. These results suggest that it may be beneficial to use suPAR as an early biomarker for identifying those individuals at highest risk for severe respiratory failure, and then treat them with anakinra. While the findings are promising, they must be validated in larger studies.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Respiratory Insufficiency/prevention & control , Aged , Aged, 80 and over , Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , COVID-19/mortality , Female , Humans , Incidence , Injections, Subcutaneous , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , Receptors, Cell Surface/blood , Receptors, Urokinase Plasminogen Activator/blood , Receptors, Urokinase Plasminogen Activator/metabolism , Respiration, Artificial , Respiratory Insufficiency/epidemiology , SARS-CoV-2 , Standard of Care , Treatment Outcome
6.
iScience ; 24(1): 101947, 2021 Jan 22.
Article in English | MEDLINE | ID: covidwho-974141

ABSTRACT

The pandemic 2019 novel coronavirus disease (COVID-19) shares certain clinical characteristics with other acute viral infections. We studied the whole-blood transcriptomic host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using RNAseq from 24 healthy controls and 62 prospectively enrolled patients with COVID-19. We then compared these data to non-COVID-19 viral infections, curated from 23 independent studies profiling 1,855 blood samples covering six viruses (influenza, respiratory syncytial virus (RSV), human rhinovirus (HRV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Ebola, dengue). We show gene expression changes in COVID-19 versus non-COVID-19 viral infections are highly correlated (r = 0.74, p < 0.001). However, we also found 416 genes specific to COVID-19. Inspection of top genes revealed dynamic immune evasion and counter host responses specific to COVID-19. Statistical deconvolution of cell proportions maps many cell type proportions concordantly shifting. Discordantly increased in COVID-19 were CD56bright natural killer cells and M2 macrophages. The concordant and discordant responses mapped out here provide a window to explore the pathophysiology of the host response to SARS-CoV-2.

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